There are three major clinical problems in treating cutaneous T-cell lymphomas (CTCL), non- Hodgkin's lymphomas characterized by inflammatory skin lesions. First, diagnosis of early-stage CTCL is difficult and takes on average six years, often delaying diagnosis until the disease becomes more aggressive. Second, 20% of early stage patients go on to progressive, often lethal disease and there is no validated way to identify patients who will progress. Third, CTCL is both a skin lymphoma and inflammatory disease. Clinical assessment of skin inflammation doesn't necessarily reflect malignant T cell burden, making determination of responses to therapy difficult. We provide pilot data that high throughput TCR CDR3 sequencing (HTS) can diagnose CTCL even in its earliest stages by identifying and quantifying malignant clonal T cells in skin lesions. We show that it permits for the first time comprehensive studies of the malignant and benign T cell infiltrate in skin lesions that may lead to methods for identifying patients who will progress. Lastly, the ability of this technique to quantify malignant T cells makes it vastly superior to clinical examination as a way to assess responses to therapy. HTS is available as both a research and clinical test but is not currently used in CTCL clinics because its utility and reliability in CTCL have not been demonstrated. We have assembled a multi-institutional, multidisciplinary collaborative team of industrial scientists, physician scientist's expert in CTCL translational research and physician's expert in the care of CTCL patients. Our Industrial Partner, Adaptive Biotechnologies, is a pioneer in HTS technology. Our Academic Partner, Brigham and Women's Hospital at Harvard Medical School, is a world recognized center for CTCL translational research. We have forged a collaboration with three of the top CTCL Clinical Care Centers in the nation to identify and supply patient samples. In Aim 1, we propose experiments designed to demonstrate that evaluation of the malignant clone, combined with percentages of the top five benign clones, definitively diagnoses CTCL even in its earliest stages and discriminates it from benign inflammatory skin diseases. In Aim 2, we will evaluate immune based parameters predictive of progression in other cancers to determine if they can identify patients who will develop progressive CTCL. In Aim 3, we will utilize HTS in three separate clinical trials to definitively demonstrate its superiority to clinical examination in assessing responses to therapy. The goal of this proposal is to demonstrate that HTS can revolutionize the way CTCL is diagnosed and monitored, transforming the care of these patients and bringing HTS into common use as a diagnostic and prognostic test in CTCL clinics.